The present invention, in some embodiments thereof, relates methods of treating cancer of the central nervous system.
Central nervous system malignant neoplasias and glioma in particular, have so far defied all current therapeutic modalities. In the last few years, an ever increasing body of data have suggested that glutamate (Glu), the major excitatory neurotransmitter in brain, plays a crucial role in the growth of malignant gliomas, their invasiveness and ability to destroy neighboring brain tissue (Lyons, et al. 2007; Sontheimer 2003) while being also the possible cause of the tumor-associated seizures that often occur in conjunction with gliomas.
Thus, studies with glioma cells in culture have shown that the cells release massive amounts of Glu resulting in elevations of the extracellular concentrations of Glu in excess of 100 μLM within hours in a space that is 1000-fold larger than the cellular volume (Ye and Sontheimer 1999). This massive release was attributed in part to a deficient Glu uptake by glioma cells attributed to the reduction-mislocalization of Glu transporters (Ye, et al. 1999). Moreover, exposure of cultured hippocampal neurons to glioma-conditioned medium caused widespread neuronal death attributed to the excitotoxic effects exerted by excess Glu (Ye and Sontheimer 1999). This neuronal death was inhibited by NMDA receptor antagonists as well as by inhibitors of the glutamate-cystine exchanger (Ye and Sontheimer 1999). The importance of this massive Glu release was explored in the context of glioma growth. It was found that increased peritumoral levels of Glu were present in the brain of rats implanted with RG2 glioma cells (Sheline, et al. 2000). Moreover, injection of C6 gliomas into rat brain striata yielded significant tumor growth only in glioma cells capable of releasing Glu (Takano, et al. 2001).
Additional findings showed that antagonists of the NMDA and AMPA receptors, two major subtypes of ionotropic Glu receptors, inhibited the proliferation (Rzeski, et al. 2002) and migration of both rat (Takano, et al. 2001) and human (Ishiuchi, et al. 2002) malignant gliomas while an antagonist of the Glu metabotropic receptor reduced glioma growth (Arcella, et al. 2005).
Several scientific reports suggested glutamate inhibitors for the treatment of gliomas include: Birmingham 2002; Ikonomidou and Turski 2002; Lutsep and Clark 2001a; Lutsep and Clark 2001b. Related patent literature include: U.S. Patent Application Number 20030050224.
PCT Publication Number WO2004/012762 teaches a method of reducing extracellular brain glutamate levels. The method comprises administering to a subject in need thereof a therapeutically effective amount of an agent capable of reducing blood glutamate levels thereby reducing extracellular brain glutamate levels. Other related publications include, Pawlik, et al. 1981, O'Kane, et al. 1999, Gottlieb, et al. 2003, (eichberg, et al. 2008 and Zlotnik, et al. 2008.